Frequent invasive procedures occur during neonatal intensive care causing pain and stress in preterm neonates during a critical period of increased brain plasticity. Repetitive painful experiences or prolonged exposure to analgesic drugs in preterm neonates may significantly alter their clinical and neurobehavioral outcomes. Analgesic practices recorded prospectively in 109 Neonatal Intensive Care Units (NICUs) showed that opioids and benzodiazepines were most commonly used, with large variations in clinical practice. No analgesia/sedation was given to 73.5 percent of neonates during NICU care or invasive procedures. A pilot randomized trial of morphine, midazolam, or placebo therapy in 69 preterm neonates showed reduced behavioral responses to pain and evidence of decreased incidence of death or neurologic injury in the morphine group. Trends for increased weight gain, earlier discharge, and other clinical outcomes support the need for and the feasibility of a definitive randomized trial. The NEOPAIN Multicenter Trial will randomize 940 ventilated neonates (24-32 weeks gestation) from 11 NICUs to receive continuous infusions of morphine or placebo. This design will provide 80 percent power for the detection of a 30 percent reduction in the composite outcome of neonatal death, Grade III or IV intraventricular hemorrhage, or periventricular leukomalacia. Data collection will include (maternal/infant) demographic, clinical and behavioral data. Other clinical outcomes include weight gain, severity of neonatal illness, and durations of NICU and hospital stay. Behavioral outcomes include neurobehavioral and psychometric testing at the time of hospital discharge. Trial coordination, data management and statistical analyses for the NOPAIN Trial are described in this application. The use of opioids (morphine and fentanyl) in preterm neonates is increasing without scientific evaluation and with scarce data on their clinical or adverse effects. The need for and clinical impact of prolonged analgesia in the NICU must be defined now before widespread use occurs. To provide data about the safety of opioid use, the effects of early pain/stress on the long-term neurobehavioral outcomes of prematurity in neonates without analgesia must be compared to the effects of analgesia use in neonates. This trial can provide those data. Thus, the results of this trial have the potential to significantly alter clinical practice in the NICU and reduce a major cause of severe morbidity and mortality in neonates.